Cocaine blocks dopamine transport in brain, a process strongly implicated in the effects of the drug. Potential candidates for the drug treatment of cocaine include dopamine transport inhibitors with slow onset times and long duration of action. Such drugs may have reduced abuse liability and confer lower risk for acquiring AIDS by frequent intravenous injections. An effective approach for identifying long-acting agents is to determine transporter occupancy of a candidate drug by PET imaging. Using [11C] WIN 35,428 to label the transporter, we monitored occupancy of two picomolar affinity transport inhibitors, indatraline and RTI-55, 24 hour after i.m. administration to 3 cynomolgus monkeys. PET imaging of the dopamine transporter was conducted with [11C] WIN 35,428 to acquire control values. Subsequently, indatraline (0.2 or 1.0 mg/kg) or RTI-55 (1 mg/kg) were administered and PET imaging was performed 24 hours later. [11C] WIN 35,428 accumulation, calculated as percent change control was reduced by 39 q 3% in putamen and 35 q 2% in caudate by indatraline and by 20 q 9% in putamen and 17 q 8% in caudate with RTI-55. To compare whether the lower affinity [11C] c]ocaine is a more sensitive indicator of dopamine transporter occupancy, a pilot study was conducted with [11C] c]ocaine, prior to and 24 hours after indatraline (1 mg/kg) was administered. The reduction observed with [11C] c]ocaine was 30 q 5% in putamen and 27 q 3% in caudate, indicating that it is not superior to [11C] WIN 35,428 for this application. These studies indicate that the PET imaging is an